Loss of Vagal Sensitivity to Cholecystokinin in Rats Born with Intrauterine Growth Retardation and Consequence on Food Intake

Abstract

Perinatal malnutrition is associated with low birth weight and an increased risk of developing metabolic syndrome in adulthood. Modification of food intake (FI) regulation was observed in adult rats born with intrauterine growth retardation induced by maternal dietary protein restriction during gestation and maintained restricted until weaning. Gastrointestinal peptides and particularly cholecystokinin (CCK) play a major role in short-term regulation of FI by relaying digestive signals to the hindbrain via the vagal afferent nerve (VAN). We hypothesized that vagal sensitivity to CCK could be affected in rats suffering from undernutrition [low protein (LP)] during fetal and postnatal life, leading to an altered gut–brain communication and impacting satiation. Our aim was to study short-term FI along with signals of appetite and satiation in adult LP rats compared to control rats. The dose–response to CCK injection was investigated on FI as well as the associated signaling pathways activated in nodose ganglia. We showed that LP rats have a reduced first-meal satiety ratio after a fasting period associated to a higher postprandial plasmatic CCK release, a reduced sensitivity to CCK when injected at low concentration and a reduced presence of CCK-1 receptor in nodose ganglia. Accordingly, the lower basal and CCK-induced phosphorylation of calcium/calmodulin-dependent protein kinase in nodose ganglia of LP rats could reflect an under-expressed vanilloid family of transient receptor potential cation channels on VAN. Altogether, the present data demonstrated a reduced vagal sensitivity to CCK in LP rats at adulthood, which could contribute to deregulation of FI reported in this model.

Neonatal Consumption of Oligosaccharides Greatly Increases L-Cell Density without Significant Consequence for Adult Eating Behavior

“…Since the perinatal environment [6,9,24,26] appears to have a long-lasting impact on each of the microbiota-EEC-brain axis actors, we had assumed that early modulation of the microbiota associated with changes in EECs could program eating behavior, a hypothesis which has remained unexplored until now. However, this hypothesis could not be corroborated in this study as adult feeding behavior did not seem to be significantly affected by early supplementation with OS, which nonetheless increased total SCFA, along with increased release of GLP-1 and PYY and L-cell density at the end of supplementation.…”

“…In fact, no difference in the expression of c-Fos was observed in the nucleus of the solitary tract in the rat’s brainstem 2 h after administering a bolus of glucose in adult rats (data not shown). It therefore seems that depending on the nature and intensity of the perinatal stressor (maternal protein restriction [9], maternal deprivation [26] or postnatal modulation of microbiota by OS) the long-lasting impact is not systematic. For the microbiota, the lack of programming could be related to an inadequacy in the timing for applying the modulation, as discussed below.…”

“…Among the environmental stressors that may have an effect, it is suggested in both animal and human studies that perinatal nutrition could program the appetite (see [5,6] for reviews). In rodents, experiments based on restricting maternal nutrition and/or manipulating litter size have demonstrated that both pre- and post-natal nutrition may alter food intake [7,8,9] and/or food preference [10] in offspring, with subsequent repercussions in adulthood. In humans, although controversial results have been observed concerning the influence of prenatal nutrition on later eating behavior (see [11] for review), some observational evidence suggests that early nutrition/growth affects appetite regulation [12,13,14] and food preference programming, as demonstrated after repeated exposure to new flavors [15].…”

“…This programming could stem from either the programming of intestinal microbiota (e.g., [24]) or the early impacts of microbiotal changes with long-lasting consequences for the peripheral neuroendocrine systems that control adult feeding behavior and/or the central sensing of it. In this respect, it is worth mentioning the ability of microbiota-modulating agents to affect the hypothalamic expression of neurogenic factor (BDNF) during the neonatal stage [25], and the potential programmable character of both the EECs [26] and the vagal sensitivity [9]. In addition, the putative ability of the gut microbiota to act through epigenetic mechanisms (see [27] for review) as well as the ability of the microbiota presence [28] and certain microbiota modulating agents [e.g., in the case of prebiotics [29,30]) to modulate some behaviors in adults mice can be cited, assuming that they are transposable in the neonatal period.…”

Maternal Microbiota Transfer Programs Offspring Eating Behavior

“…However, the ability of early gut microbiota to program the eating behavior of adults is poorly studied ( van de Wouw et al, 2017 ). This issue clearly deserves further study given the large body of evidence showing that eating behavior and the neural circuits involved in its control, i.e., the vagus nerve, hypothalamus, and reward circuits, can be programmed early in life through nutrition and the environment factors ( Coupe et al, 2010 ; Ross and Desai, 2014 ; Ndjim et al, 2017 ; Paradis et al, 2017 ).…”